Postural tachycardia syndrome (POTS) is the most common form of orthostatic intolerance, affecting an estimated 500,000 Americans, principally young women. Patients typically experience symptoms of excessive sympathetic activation with physical or emotional exertion. Upright heart rate and plasma norepinephrine are elevated. Many patients are also disabled by chronic fatigue. No genuinely effective therapy for POTS has emerged. The long-term goal of this project remains to find the fundamental causes of orthostatic intolerance and discover appropriate treatment. The most constant hemodynamic feature in POTS is hypovolemia, but the cause of this abnormality has been elusive. Our recent studies in these patients have motivated us to propose a novel dopaminergic mechanism contributing to the pathophysiology of POTS. POTS patients appear to have an impaired capacity to conserve sodium. We find that dopamine levels are unexpectedly elevated in both plasma and urine of these patients. Several investigators have implicated dopamine in the control of natriuresis in other disorders. Approximately 50% of sodium excretion appears to be under dopaminergic regulation. To test the hypothesis that impaired sodium handling by renal dopamine contributes to the hypovolemia of POTS, investigations of POTS patients and normal controls will be undertaken with careful control of sodium intake and monitoring of urinary sodium and dopamine excretion. Initial studies will determine the extent to which sodium administration engages systemic and renal dopamine and stimulates natriuresis in POTS. Additional specific aims are directed at assessing the relative dopaminergic and natriuretic responses to interventions aimed at (1) increasing plasma dopa, (2) blocking L-aromatic amino acid decarboxylase, and (3) antagonizing renal dopamine. These studies should define the role of dopamine in POTS. If hyperdopaminergic renal mechanisms do indeed underlie the hypovolemia of POTS, a specific and safe pharmacotherapy, carbidopa, will be tested for efficacy in overcoming the volume deficit in this disorder and improving the functional capacity of affected patients. PUBLIC HEALTH RELEVANCE: Postural tachycardia syndrome (POTS) is a common disorder in young women, impairing their functional capacity through symptoms like weakness, palpitations, fatigue, headaches, and exercise intolerance. The purpose of this grant proposal is to understand the abnormally low volume of blood in these patients. This knowledge will permit trials of treatment targeted at making the blood volume normal and improving symptoms in these patients